LRFN5 and OLFM4 in Methamphetamine-Induced Psychosis

Serum LRFN5 and OLFM4 Levels in Methamphetamine Use Disorder and Methamphetamine-Induced Psychotic Disorder: A Cross-Sectional Case-Control Study

This cross-sectional observational case-control study aimed to examined serum levels of leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5) and olfactomedin-4 (OLFM4) levels in methamphetamine use disorder (MUD), methamphetamine-induced psychotic disorder (MP), and healthy control (HC) groups. The study also aimed to assessed systemic inflammation using the Aggregate Index of Systemic Inflammation (AISI) and examined associations between biomarkers and clinical symptom severity, including Insight Assessment Scale (IAS) and Positive and Negative Syndrome Scale (PANSS) scores.

Study Overview

• Status: Completed
• Conditions: Methamphetamine Use Disorder; Methamphetamine-induced Psychosis

Detailed Description

Methamphetamine is a potent central nervous system stimulant associated with addiction, neurotoxicity, and increased risk of psychosis. Chronic exposure affects dopaminergic systems in the mesolimbic and striatal pathways, potentially contributing to sensitization and psychotic symptom development. Methamphetamine-induced psychotic disorder (MP) occurs in a substantial proportion of users, yet individual vulnerability varies. Biological markers that may predict psychosis in methamphetamine users remain insufficiently studied.

Leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5) is a transmembrane synaptic adhesion molecule involved in synapse development, plasticity, and neuroimmune regulation. It contributes to excitatory and inhibitory synaptic differentiation and may influence neuroinflammatory responses. Olfactomedin-4 (OLFM4) is a neutrophil-specific glycoprotein involved in innate immunity, apoptosis regulation, inflammation, and glutamatergic synaptic modulation. These two markers are located in relatively close chromosomal regions and may demonstrate coordinated biological behavior.

To date, LRFN5 and OLFM4 have not been investigated in methamphetamine use disorder (MUD) or MP. This study is designed to compare serum levels of LRFN5 and OLFM4 among subjects with MP, subjects with MUD, and healthy controls (HC) subjects. A secondary objective was to evaluate associations between LRFN5, OLFM4 levels, psychotic symptom severity, and systemic inflammation, and to assess its potential predictive value for MP diagnosis.

Participants were planned to be consecutive inpatients diagnosed with MUD or MP according to the American Psychiatric Association's Fifth Edition Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR). Participant recruitment began on September 1, 2025, and is planned to be completed on April 1, 2026. All patients were selected/will be selected from those admitted to Elazığ Mental Health and Diseases Hospital. The HC group consisted of individuals without current or past psychiatric disorders or significant medical illnesses. Adult male participants aged 18-65 were included.

Venous blood samples were collected/will be collected at hospital admission prior to initiation of treatment. Samples were/will be centrifuged within 30 minutes and serum was stored at -80°C until analysis. Serum LRFN5 and OLFM4 levels were/will be measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's instructions. Routine biochemical analyses and urine toxicology screening were/will be also performed. The Aggregate Index of Systemic Inflammation (AISI) was/will be calculated as (neutrophils × monocytes × platelets) / lymphocytes.

Psychotic symptom severity in the MP group was/will be assessed using the Positive and Negative Syndrome Scale (PANSS). Insight in the MP group was/will be assessed using the Insight Assessment Scale (IAS). Sociodemographic variables and clinical characteristics, including self-mutilation history, drug use onset age, duration of methamphetamine use, and smoking status were/will be recorded.

The study was/will be conducted in accordance with the Declaration of Helsinki and approved by the relevant institutional ethics committee. All participants provided/will provide written informed consent prior to participation.

• Study Type: Observational
• Enrollment (Actual): 111

Contacts and Locations

Study Locations

• Turkey (Türkiye)
  • Elâzığ
    • Elâzığ, Elâzığ, Turkey (Türkiye), 23200
      • Elazığ Mental Health and Diseases Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population consisted/will be consisted of adult male inpatients aged 18-65 years who were admitted to Elazığ Mental Health and Diseases Hospital.

The MP group included/will include consecutive inpatients diagnosed with methamphetamine-induced psychotic disorder (MP) and the methamphetamine use disorder (MUD) group included/will include consecutive inpatients diagnosed with MUD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR).

Both patient groups consisted of active methamphetamine users and were hospitalized for clinical management at the time of assessment. Urine toxicology screening was performed at admission to confirm substance use status.

The Healthy Control (HC) group consisted of adult male individuals without current or past psychiatric disorders and without substance use disorders, matched to patient groups in terms of age and body mass index. HCs had no significant medical illnesses.

Description

1. For Methamphetamine Use Disorder (MUD) Group:

   *Inclusion Criteria:

   • Diagnosis of MUD according to DSM-5-TR
   • Medication-free for at least one month prior to admission
   • Age ≥ 18 years and <65 years
   • Provided informed consent

   For Methamphetamine Use Disorder (MUD) Group:

   *Exclusion Criteria:

   • Hypertension

   • Diabetes mellitus
   • Chronic kidney disease
   • Rheumatoid arthritis
   • Systemic lupus erythematosus
   • Cardiac illness
   • Severe neurological disorders
   • Immunological or systemic illness
   • Primary psychiatric disorders other than MUD
   • Alcohol use disorder

2. For Methamphetamine-Induced Psychotic Disorder (MP) Group:

   *Inclusion Criteria:

   • Diagnosis of MP according to DSM-5-TR
   • Medication-free for at least one month prior to admission
   • Age ≥ 18 years and <65 years
   • Provided informed consent

   For Methamphetamine-Induced Psychotic Disorder (MP) Group:

   *Exclusion Criteria:

   • Hypertension
   • Diabetes mellitus
   • Chronic kidney disease
   • Rheumatoid arthritis
   • Systemic lupus erythematosus
   • Cardiac illness
   • Severe neurological disorders
   • Immunological or systemic illness
   • Primary psychiatric disorders other than MP
   • Alcohol use disorder

3. For Healthy Control Group:

   *Inclusion Criteria:

   • No psychiatric diagnosis
   • No systemic or immunological illness
   • Medication-free for at least one month
   • Age ≥ 18 years and <65 years
   • Provided informed consent

   For Healthy Control Group:

   *Exclusion Criteria:

   • Hypertension

   • Diabetes mellitus
   • Chronic kidney disease
   • Rheumatoid arthritis
   • Systemic lupus erythematosus
   • Cardiac illness
   • Severe neurological disorders
   • Immunological or systemic illness
   • Primary psychiatric disorders other than schizophrenia
   • Alcohol/drug/substance use

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Methamphetamine Use Disorder; Adult participants (18-65 years) diagnosed with Methamphetamine Use Disorder according to DSM-5-TR criteria. Participants were/will be evaluated at hospital admission (baseline). No intervention was/will be assigned by the study protocol. Blood samples were/will be collected for measurement of serum LRFN5 and OLFM4 levels and complete blood count parameters. No psychometric scales were/will be administered to this group. Sociodemographic and clinical data were/will be recorded for all participants.
Methamphetamine-Induced Psychotic Disorder; Adult participants (18-65 years) diagnosed with Methamphetamine-Induced Psychotic Disorder according to DSM-5-TR criteria. Participants were/will be evaluated at hospital admission (baseline). No intervention was/will be assigned by the study protocol. Blood samples were/will be collected for measurement of serum LRFN5 and OLFM4 levels and complete blood count parameters. Psychotic symptom severity was/will be assessed using the Positive and Negative Syndrome Scale (PANSS). Insight Assessment Scale was/will be used to measure the insight level. Sociodemographic and clinical data were/will be recorded for all participants.
Healthy Control; Healthy control adult participants (18-65 years) without any current or past psychiatric disorder. No intervention was administered as part of the research protocol. Participants underwent a baseline clinical evaluation and provided a single blood sample for measurement of serum α-N-acetylgalactosaminidase levels and complete blood count inflammatory markers. Sociodemographic and clinical data were recorded for all participants. As of January 6, 2026, the recruitment of healthy control participants has been completed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5)	Serum leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5) levels measured by ELISA (pg/ml)	At hospital admission (baseline)
Olfactomedin-4 (OLFM4)	Serum olfactomedin-4 (OLFM4) levels measured by ELISA (pg/ml)	At hospital admission (baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aggregate Index of Systemic Inflammation (AISI)	Aggregate Index of Systemic Inflammation (AISI) is calculated using the following formula: (neutrophils × monocytes × platelets) / (lymphocytes). All the parameters mentioned here are complete blood count parameters.	At hospital admission (baseline)
Positive and Negative Syndrome Scale (PANSS) Score	Positive and Negative Syndrome Scale (PANSS) was developed to assess positive and negative symptoms and general psychopathology in patients with schizophrenia-spectrum disorder, and to measure the level of these symptoms. It is administered via a semi-structured interview, taking into account the last week. Information can also be obtained from the patient's relatives and healthcare staff. It consists of a total of 30 items: 7 items addressing positive symptoms, 7 addressing negative symptoms, and 16 addressing general psychopathology symptoms. Each item is scored from 1 to 7, and the scores are summed for the final score. This scale was only administered to the methamphetamine-induced psychotic disorder group.	At hospital admission (baseline)
Insight Assessment Scale (IAS)	It was reported that insight cannot be evaluated as either present or absent, and it was defined it as a three-way process consisting of compliance with treatment, awareness of the illness, and accurate recognition of psychotic experiences. Based on these components, Insight Assessment Scale (IAS) was developed as a clinician-administered scale that quantitatively assesses insight for individuals with psychosis. IAS is an 8-question, clinician-administered, semi-structured scale. "Treatment acceptance"(1a), " treatmentrequest" (1b), "knowledge of illness" (2a), "knowledge of mental illness" (2b), "explanation of illness" (2c), "In addition to the 7 subscales titled "believing in the truth of the delusion" (3a), "explaining their experiences" (3b), there is a subscale titled "reaction to disbelief". The highest total score with this question is 18. A high score indicates a high level of insight.	At hospital admission (baseline)

Collaborators and Investigators

• Sponsor: Elazığ Mental Health and Diseases Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2025
• Primary Completion (Actual): April 1, 2026
• Study Completion (Actual): April 1, 2026

Study Registration Dates

• First Submitted: February 27, 2026
• First Submitted That Met QC Criteria: February 27, 2026
• First Posted (Actual): March 4, 2026

Study Record Updates

• Last Update Posted (Actual): September 10, 2026
• Last Update Submitted That Met QC Criteria: September 8, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Methamphetamine; Psychotic Disorder; Psychostimulants; LRFN5; OLFM4; Methamphetamine Psychosis
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Psychotic Disorders
• Other Study ID Numbers: EMHDH-2025/26-METH-LRFN5-OLFM4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Deidentified individual participant data (IPD) underlying the results reported in this study [including demographic variables, serum leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5) and Olfactomedin-4 (OLFM4) levels, complete blood count parameters, and Positive and Negative Syndrome Scale (PANSS) and Insight Assessment Scale (IAS)] will be made available to qualified researchers upon reasonable request for academic purposes.

Data will be shared after removal of all direct identifiers and in accordance with applicable ethical approvals and data protection regulations. Access to the data will require a methodologically sound research proposal and a data use agreement. Requests should be directed to the corresponding author.

• IPD Sharing Time Frame: Data will be available beginning 6 months after publication and will remain available for 5 years.
• IPD Sharing Access Criteria: Access will be granted to researchers who provide a methodologically sound proposal. Requests must be approved by the principal investigator and may require a data use agreement in accordance with institutional and ethical regulations.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No